Circadian rhythms, sleep, and substance abuse

Substance abuse is linked to numerous mental and physical health problems, including disturbed sleep. The association between substance use and sleep appears to be bidirectional, in that substance use may directly cause sleep disturbances, and difficulty sleeping may be a risk factor for relapse to substance use. Growing evidence similarly links substance use to disturbances in circadian rhythms, although many gaps in knowledge persist, particularly regarding whether circadian disturbance leads to substance abuse or dependence. Given the integral role circadian rhythms play in regulating sleep, circadian mechanisms may account in part for sleep-substance abuse interactions. Furthermore, a burgeoning research base supports a role for the circadian system in regulating reward processing, indicating that circadian mechanisms may be directly linked to substance abuse independently of sleep pathways. More work in this area is needed, particularly in elucidating how sleep and circadian disturbance may contribute to initiation of, and/or relapse to, substance use. Sleep and circadian-based interventions could play a critical role in the prevention and treatment of substance use disorders.     

Circadian rhythms and sleep in bipolar disorder

Murray G, Harvey A. Circadian rhythms and sleep in bipolar disorder.
Bipolar Disord 2010: 12: 459–472. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objective: Biological rhythm pathways are highlighted in a number of etiological models of bipolar disorder, and the management of circadian instability appears in consensus treatment guidelines. There are, however, significant conceptual and empirical limitations on our understanding of a hypothesised link between circadian, sleep, and emotion regulation processes in bipolar disorder. The aim of this article is to articulate the limits of scientific knowledge in relation to this hypothesis. Methods: A critical evaluation of various literatures was undertaken. The basic science of circadian and sleep processes, their involvement in normal emotion regulation, and the types of evidence suggesting circadian/sleep involvement in bipolar disorder are reviewed. Results: Multiple lines of evidence suggest that circadian and sleep‐wake processes are causally involved in bipolar disorder. These processes demonstrably interact with other neurobiological pathways known to be important in bipolar disorder, but are unique in that they are open to behavioural manipulation. Conclusion: Further research into biological rhythm pathways to bipolar disorder is warranted. Person‐environment feedback loops are fundamental to circadian adaptation, and models of circadian pathogenesis (and treatment) should recognize this complexity.     

Effects of menstrual cycle phase and oral contraceptives on alertness, cognitive performance, and circadian rhythms during sleep deprivation.

The influence of menstrual cycle phase and oral contraceptive use on neurobehavioral function and circadian rhythms were studied in healthy young women (n = 25) using a modified constant routine procedure during 24 h of sleep deprivation. Alertness and performance worsened across sleep deprivation and also varied with circadian phase. Entrained circadian rhythms of melatonin and body temperature were evident in women regardless of menstrual phase or oral contraceptive use. No significant difference in melatonin levels, duration, or phase was observed between women in the luteal and follicular phases, whereas oral contraceptives appeared to increase melatonin levels. Temperature levels were higher in the luteal phase and in oral contraceptive users compared to women in the follicular phase. Alertness on the maintenance of wakefulness test and some tests of cognitive performance were poorest for women in the follicular phase especially near the circadian trough of body temperature. These observations suggest that hormonal changes associated with the menstrual cycle and the use of oral contraceptives contribute to changes in nighttime waking neurobehavioral function and temperature level whereas these factors do not appear to affect circadian phase.     

Self-reported sleep across the menstrual cycle in young, healthy women

OBJECTIVE: To establish the association between subjective sleep and phase of the menstrual cycle in healthy, young, ovulating women. METHODS: Twenty-six women (mean age: 21 years) who did not suffer from any menstrual-associated disorders, and in whom we had detected ovulation, completed daily questionnaires about their sleep over 1 month. RESULTS: The women reported a lower sleep quality over the 3 premenstrual days and 4 days during menstruation, compared to the mid-follicular and early/mid luteal phases. Total sleep time, sleep onset latency, number and duration of awakenings, and morning vigilance were not affected by the menstrual cycle. CONCLUSION: The normal, ovulatory cycle is associated with changes in the perception of sleep quality but not sleep continuity in healthy, young women. The temporal relationship of sleep complaints with menstrual phase should be considered in the evaluation of sleep disorders, particularly insomnia, in women.     

Cortisol circadian rhythms during the menstrual cycle and with sleep deprivation in premenstrual dysphoric disorder and normal control subjects.

BACKGROUND: In this study we extended previous work by examining whether disturbances in the circadian rhythms of cortisol during the menstrual cycle distinguish patients with premenstrual dysphoric disorder (PMDD) from normal control (NC) subjects. In addition, we tested the differential response to the effects of early and late partial sleep deprivation on cortisol rhythms. METHODS: In 15 PMDD and 15 NC subjects we measured cortisol levels every 30 min from 6:00 PM to 9:00 AM during midfollicular (MF) and late luteal (LL) menstrual cycle phases and also during a randomized crossover trial of early (sleep 3:00 AM-7:00 AM) versus late (sleep 9:00 PM-1:00 AM) partial sleep deprivation administered in two subsequent and separate luteal phases. RESULTS: In follicular versus luteal menstrual cycle phases we observed altered timing but not quantitative measures of cortisol secretion in PMDD subjects, compared with NC subjects: in the LL versus MF phase the cortisol acrophase was a mean of 1 hour earlier in NC subjects, but not in PMDD subjects. The effect of sleep deprivation on cortisol timing measures also differed for PMDD versus NC subjects: during late partial sleep deprivation (when subjects' sleep was earlier), the cortisol acrophase was almost 2 hours earlier in PMDD subjects. CONCLUSIONS: Timing rather than quantitative measures of cortisol secretion differentiated PMDD subjects from NC subjects both during the menstrual cycle and in response to early versus late sleep deprivation interventions.     

Circadian rhythms

Circadian rhythms are a ubiquitous adaptation of eukaryotic organisms to the most reliable and predictable of environmental changes, the daily cycles of light and temperature. Prominent daily rhythms in behavior, physiology, hormone levels and biochemistry (including gene expression) are not merely responses to these environmental cycles, however, but embody the organism's ability to keep and tell time. At the core of circadian systems is a mysterious mechanism, located in the brain (actually the Suprachiasmatic nucleus of the hypothalamus) of mammals, but present even in unicellular organisms, that functions as a clock. This clock drives circadian rhythms. It is independent of, but remains responsive to, environmental cycles (especially light). The interest in temporal regulation — its organization, mechanism and consequences — unites investigators in diverse disciplines studying otherwise disparate systems. This diversity is reflected in the brief reviews that summarize the presentations at a meeting on circadian rhythms held in New York City on October 31, 1992. The meeting was sponsored by the Fondation pour l'Étude du Systéme Nerveux (FESN) and followed a larger meeting held 18 months earlier in Geneva, whose proceedings have been published (M. Zatz (Ed.), Report of the Ninth FESN Study Group on ‘Circadian Rhythms’, Discussions in Neuroscience, Vol. VIII, Nos. 2 + 3, Elsevier, Amsterdam, 1992). Some speakers described progress made in the interim, while others addressed aspects of the field not previously covered.     

Circadian rhythms, aging and memory

In human beings and animal models, cognitive performance is often impaired in natural and experimental situations where circadian rhythms are disrupted. This includes a general decline in cognitive ability and fragmentation of behavioural rhythms in the aging population of numerous species. There is some evidence that rhythm disruption may lead directly to cognitive impairment; however, this causal link has not been made for effects due to aging. We have tested this link by examining rhythms and performance on contextual conditioning with the conditioned place preference task, in elderly, age-matched hamsters. Young healthy hamsters developed a preference for a context that is paired with the opportunity to engage in wheel-running (experiment 1). Aged animals with consolidated locomotor rhythms developed similar degrees of preference, whereas the age-matched hamsters with fragmented rhythms did not (experiment 2). The degree of preference was also correlated with activity amplitude. These results support the notion that age-related rhythm fragmentation contributes to the age-related memory decline.     

Diurnal fluctuation of sleep propensity across the menstrual cycle

Most women experience sleep changes across the menstrual cycle. We applied the ultra-short sleep-wake schedule to healthy females to compare their 24-h sleep propensity rhythms in the follicular and luteal phases. The daytime (09.00-16.30 h) subjective sleepiness and the number of slow wave sleep-containing nap trials increased in the luteal phase compared to the follicular phase, but the mean sleep propensity did not change. During the periods of 17.00-00.30 h and 01.00-08.30 h there were no differences between the two phases. These results suggest that increased daytime sleepiness in the luteal phase may be related to brain mechanisms controlling slow wave sleep.     

Circadian rhythms in the mouse reproductive axis during the estrous cycle and pregnancy

Molecular and behavioral timekeeping is regulated by the circadian system which includes the brain's suprachiasmatic nucleus (SCN) that translates environmental light information into neuronal and endocrine signals aligning peripheral tissue rhythms to the time of day. Despite the critical role of circadian rhythms in fertility, it remains unexplored how circadian rhythms change within reproductive tissues during pregnancy. To determine how estrous cycle and pregnancy impact phase relationships of reproductive tissues, we used PER2::Luciferase (PER2::LUC) circadian reporter mice and determined the time of day of PER2::LUC peak (phase) in the SCN, pituitary, uterus, and ovary. The relationships between reproductive tissue PER2::LUC phases changed throughout the estrous cycle and late pregnancy and were accompanied by changes to PER2::LUC period in the SCN, uterus, and ovary. To determine if the phase relationship adaptations were driven by sex steroids, we asked if progesterone, a hormone involved in estrous cyclicity and pregnancy, could regulate Per2‐luciferase expression. Using an in vitro transfection assay, we found that progesterone increased Per2‐luciferase expression in immortalized SCN (SCN2.2) and arcuate nucleus (KTAR) cells. In addition, progesterone shortened PER2::LUC period in ex vivo uterine tissue recordings collected during pregnancy. As progesterone dramatically increases during pregnancy, we evaluated wheel‐running patterns in PER2::LUC mice. We confirmed that activity levels decrease during pregnancy and found that activity onset was delayed. Although SCN, but not arcuate nucleus, PER2::LUC period changed during late pregnancy, onset of locomotor activity did not correlate with SCN or arcuate nucleus PER2::LUC period.     

Objective sleep interruption and reproductive hormone dynamics in the menstrual cycle

ObjectivesWomen report greater sleep disturbance during the premenstrual phase of the menstrual cycle and during menses. However, the putative hormonal basis of perceived menstrual cycle-related sleep disturbance has not been investigated directly. We examined associations of objective measures of sleep fragmentation with reproductive hormone levels in healthy, premenopausal women.MethodsTwenty-seven women with monthly menses had hormone levels measured at two time points during a single menstrual cycle: the follicular phase and the peri-ovulatory to mid-luteal phase. A single night of home polysomnography (PSG) was recorded on the day of the peri-ovulatory/mid-luteal-phase blood draw. Serum progesterone, estradiol, and estrone levels concurrent with PSG and rate of change in progesterone (PROGslope) from the follicular blood draw to PSG were correlated with log-transformed wake after sleep onset (lnWASO%) and number of wakes/hour of sleep (lnWake-Index) using linear regression.ResultsSleep was more fragmented in association with a steeper PROGslope (lnWASO% p = 0.016; lnWake-Index p = 0.08) and higher concurrent estrone level (lnWASO% p = 0.03; lnWake-Index p = 0.01), but the effect of estrone on WASO was lost after accounting for PROGslope. WASO% and Wake-Index were not associated with concomitant progesterone or estradiol levels.ConclusionsA steeper rate of rise in progesterone levels from the follicular phase through the mid-luteal phase was associated with significantly greater WASO, establishing a link between reproductive hormone dynamics and sleep fragmentation in the luteal phase of the menstrual cycle.     

Circadian rhythms and depression

The degree to which nature's cycles influence our body is now obvious, owing to the recent progress of chronobiology. It seems thus that the harmonious internal organization of our circadian rhythms depends on the dual influence of the internal clocks as well as the external temporal informations. These endogenous pacemakers, able to spontaneously generate a rhythmicity the period of which is close to 24 hours, could be triggered by environmental informations, such as light/dark or sleep/Wake cycles, on a 24 hours schedule. The disruption of this entrainment could be involved in major affective disorders. This internal or external desynchronisation seems thus to be the central concept of different models for depression. The internal coincidence model suggests that a phase advance of the strong oscillator in reference to the weak oscillator causes depression. An external coincidence model suggests that depression is caused when light/dark cycle or photoperiod provide too little illumination during a critical photosensitive interval which could be located in the second half of the night. At last, a model comparing the biological rhythms of depressed patients and of healthy volunteers during temporal isolation, suggests that the internal clocks of depressed subjects could be temporarily "blind" to environmental time cues involving internal desynchronisation. These emerging findings should open a new therapeutic approach for depression.     

Nocturnal polysomnographic sleep across the menstrual cycle in premenstrual dysphoric disorder

ObjectivesWomen with premenstrual dysphoric disorder (PMDD) experience disturbed mood, altered melatonin circadian rhythms, and frequent reports of insomnia during the luteal phase (LP) of their menstrual cycle. In this study we aimed to investigate nocturnal polysomnographic (PSG) sleep across the menstrual cycle in PMDD women and controls.MethodsSeven PMDD women who indicated insomnia during LP, and five controls, spent every third night throughout a complete menstrual cycle sleeping in the laboratory.ResultsIn PMDD and controls progesterone and core body temperature (BT_core) were elevated during LP compared to the follicular phase (FP). Stage 2 sleep showed a significant main effect of menstrual phase and was significantly increased during mid-LP compared to early-FP in both groups. Rapid eye movement (REM) sleep for both groups was decreased during early-LP compared to early-FP. Slow wave sleep (SWS) was significantly increased, and melatonin significantly decreased, in PMDD women compared to controls.ConclusionsPMDD women who experience insomnia during LP had decreased melatonin secretion and increased SWS compared to controls. The sleep and melatonin findings in PMDD women may be functionally linked. Results also suggest an altered homeostatic regulation of the sleep–wake cycle in PMDD, perhaps implicating melatonin in the homeostatic process of sleep–wake regulation.     

Hormones, behaviour and the menstrual cycle

To date therefore, no consistent hormonal abnormality has been linked with premenstrual affective, physical or behavioural changes and, in turn, no consistent adverse behaviour has been positively linked with any particular menstrual cycle phase. At the same time, the proportion of actively menstruating women reported to identify premenstrual changes of a severity sufficient to warrant the illness label continues to fall so that a figure somewhere between 2 and 8% seems to be established where once figures in excess of 70% were claimed. The implication would seem to be that more thorough assessment of the relatively small number of women who are clearly identifiable as sufferers from cyclically-mediated symptoms might well cast light on possible hormonal-behavioural links where larger, less careful studies of heterogeneous samples of women have failed to do so. The great majority of women appear to negotiate the premenstrual phase of their menstrual cycles with little or no impairment or difficulty. A small number appear to be vulnerable and the possibility that it is, at least in part, a biological vulnerability is hinted at in those reports which tentatively suggest that some women who are especially prone to post-partum 'blues' and who are particularly sensitive to oral contraceptives may be especially prone to premenstrual tension. Finally, the ubiquity of premenstrually perceived 'changes' as distinct from 'symptoms' raises the possibility that the extent to which a woman experiences various premenstrual changes as complaint or illness may depend 'more on her basic personality and the circumstances in which she experiences the cyclical changes than on the underlying cyclical mechanism'.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sex and modulatory menstrual cycle effects on sleep related memory consolidation

The benefit of sleep in general for memory consolidation is well known. The relevance of sleep characteristics and the influence of hormones are not well studied. We explored the effects of a nap on memory consolidation of motor (finger-tapping-task) and verbal (associated-word-pairs) tasks in following settings: A: young, healthy males and females during early-follicular phase (n=40) and B: females during mid-luteal and early-follicular phase in the menstrual cycle (n=15). We found a sex and in women a menstrual cycle effect on memory performance following a nap. Men performed significantly better after a nap and women did so only in the mid-luteal phase of their menstrual cycle. Only the men and the women in their mid-luteal phase experienced a significant increase in spindle activity after learning. Furthermore, in women estrogen correlated significantly with the offline change in declarative learning and progesterone with motor learning. The ratio of the 2nd and 4th digit, which has been associated to fetal sex hormones and cognitive sex differences, significantly predicted the average performance of the female subjects in the learning tasks. Our results demonstrate that sleep-related memory consolidation has a higher complexity and more influencing factors than previously assumed. There is a sex and menstrual cycle effect, which seems to be mediated by female hormones and sleep spindles. Further, contrary to previous reports, consolidation of a simple motor task can be induced by a 45 min NREM sleep nap, thus not dependent on REM sleep.     

Circadian rhythms and cardiovascular health

The functional organization of the cardiovascular system shows clear circadian rhythmicity. These and other circadian rhythms at all levels of organization are orchestrated by a central biological clock, the suprachiasmatic nuclei of the hypothalamus. Preservation of the normal circadian time structure from the level of the cardiomyocyte to the organ system appears to be essential for cardiovascular health and cardiovascular disease prevention. Myocardial ischemia, acute myocardial infarct, and sudden cardiac death are much greater in incidence than expected in the morning. Moreover, supraventricular and ventricular cardiac arrhythmias of various types show specific day-night patterns, with atrial arrhythmias--premature beats, tachycardias, atrial fibrillation, and flutter - generally being of higher frequency during the day than night--and ventricular fibrillation and ventricular premature beats more common, respectively, in the morning and during the daytime activity than sleep span. Furthermore, different circadian patterns of blood pressure are found in arterial hypertension, in relation to different cardiovascular morbidity and mortality risk. Such temporal patterns result from circadian periodicity in pathophysiological mechanisms that give rise to predictable-in-time differences in susceptibility-resistance to cyclic environmental stressors that trigger these clinical events. Circadian rhythms also may affect the pharmacokinetics and pharmacodynamics of cardiovascular and other medications. Knowledge of 24-h patterns in the risk of cardiac arrhythmias and cardiovascular disease morbidity and mortality plus circadian rhythm-dependencies of underlying pathophysiologic mechanisms suggests the requirement for preventive and therapeutic interventions is not the same throughout the day and night, and should be tailored accordingly to improve outcomes.     

Diurnal fluctuation of sleep propensity and hormonal secretion across the menstrual cycle.

BACKGROUND: The fact that most women experience sleep changes across the menstrual cycle is thought to be associated with changes in circadian rhythms; however, few studies have investigated this relationship. METHODS: We applied an ultrashort sleep-wake schedule to eight healthy women and studied diurnal fluctuations in sleep propensity, sleepiness, rectal temperature, and serum concentrations of melatonin, thyroid-stimulating hormone, and cortisol in the follicular and luteal phases. RESULTS: In the luteal phase, amplitude of core body temperature, total melatonin secretions, and amplitudes of TSH and cortisol rhythms were significantly decreased, whereas sleepiness and occurrence of slow-wave sleep during the daytime were significantly increased. Differences in the amount of daytime slow-wave sleep across the menstrual cycle were positively correlated with differences in the daily mean rectal temperature. CONCLUSIONS: The findings suggest that the amplitude of circadian oscillation may be dampened in the luteal phase. Increased daytime sleepiness in the luteal phase may be associated with increased daytime slow-wave sleep, due possibly to changes in thermoregulation in the luteal phase.     

Association between sleep duration and menstrual cycle irregularity in Korean female adolescents

ObjectiveThe association between sleep and the menstrual cycle in the adolescent population has been scarcely studied. This study aimed to investigate the association between sleep duration and menstrual cycle irregularity among female adolescents using nationwide representative data from the South Korean population.MethodsThis population-based, cross-sectional study used the data collected from Korea National Health and Nutrition Examination Survey 2010–2012, and the data from 801 female adolescents were analyzed. Hierarchical multivariable logistic regression analysis was performed to assess the risk of menstrual cycle irregularity in relation to sleep duration.ResultsSubjects with menstrual cycle irregularity accounted for 15% (N = 120). The mean sleep duration in subjects with menstrual cycle irregularity was significantly shorter than that in those without (p = 0.003). Menstrual cycle irregularity prevalence tended to decrease as sleep duration increased (p for trend = 0.004), which was significantly different based on sleep duration and presence of depressive mood (p = 0.011). Sleep duration ≤5 h per day was significantly associated with increased risk of menstrual cycle irregularity compared with that in the subjects whose sleep duration is ≥8 h per day even after adjusting for confounding variables. The odds ratios of menstrual cycle irregularity tended to increase for shorter sleep duration in all adjusted models.ConclusionThis study found a significant inverse association between sleep duration and menstrual cycle irregularity among Korean female adolescents. Increasing sleep duration is required to improve the reproductive health of female adolescents.